In July 2023, a 39-year-old Chinese engineer, presented with a month-long history of fever and a non-tender, non-pruritic rash affecting all four limbs and his back. Upon admission to the haematology unit of Queen Mary Hospital, he denied any recent trauma or symptoms related to the respiratory, neurological, or urinary systems. Moreover, the patient indicated no recent travel, hiking, freshwater exposure, or insect bites.
The patient has a medical history of hypertension and T-cell acute lymphoblastic leukaemia (T-ALL), which was diagnosed in November 2018. He underwent a matched unrelated donor haematopoietic stem cell transplantation on 29th June 2019 and is currently in complete remission. He developed gut and liver graft-versus-host disease (GVHD), for which he requires ongoing immunosuppressive therapy. A recent bone marrow examination on 19th June 2020, showed regenerating marrow with no signs of recurrence. The patient's current medication regimen includes Acyclovir, Amlodipine, Betaloc, Pepcidine, Trimethoprim-sulfamethoxazole (TMP-SMX), Ursodeoxycholic acid, Mycophenolate mofetil, Prednisolone, Ruxolitinib phosphate, and Sirolimus. The dosage of these medications has remained unchanged for the past 6 months. Regarding his social background, the patient never smokes and denied any regular alcohol or drug use. He also denied taking any over-the-counter medication or traditional Chinese medication.
Physical examination revealed multiple erythematous non-tender non-pruritic nodules over four limbs and painful swelling over the right second to fourth metatarsal pharyngeal joints (Fig. 1–3). There were no palpable cervical, axillary, or inguinal lymph nodes. The oral mucosal surface and conjunctiva were not involved. There were no obvious nail changes.
Initial investigations include:
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Clinical photographs
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Blood tests: Complete blood count, liver and renal function test, lactate dehydrogenase (LDH), C-reactive protein (CPR), Erythrocytes sedimentation rate (ESR), creatine kinase (CK), Sirolimus level, autoimmune markers (Table 1)
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Microbiological workup including bacterial and fungal culture (Table 2)
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Skin biopsy
Table 1
Investigations | Result (reference range) |
Haemoglobin | 10.1 g/dL (13.3–17.1) |
WBC | 6.38 x 109/L (3.89–9.93) |
Platelet | 216 x 109/L (167–396) |
Sodium | 137 mmol/L (135–145) |
Potassium | 4.1 mmol/L (3.5–5.5) |
Creatinine | 142 µmol/L (67–109) |
eGFR (CKD-EPI) | 53 (> 90) |
Total bilirubin | 7 umol/L (4–23) |
Alkaline Phosphatase | 92 U/L (42–110) |
Alanine Aminotransferase | 45 U/L (8–58) |
Aspartate Aminotransferase | 33 U/L (15–38) |
Albumin adjusted calcium | 2.21 mmol/L (2.11–2.55) |
CRP | 3.02 mg/dL (< 0.5) |
ESR | > 140 mm/h (< 7) |
Creatine kinase | 166 U/L (65–355) |
Sirolimus level | 10 (Therapeutic 5–15 ug/L) |
LDH | 360 U/L (118–221) |
Hepatitis B screen (HBsAg and Anti-HBc) | Non-reactive |
Autoimmune markers including ANA, Anti-dsDNA, ANCA and Anti-ENA | Negative |
Table 2
Cytomegalovirus Antigen pp65 | Not detected |
Cryptococcal antigen | Negative |
Aspergillus antigen | Negative |
Epstein Barr Virus DNA PCR: | < 100 IU/mL |
Blood culture | No growth |
Urine culture | No growth |
HIV antigen and Anti-HIV 1/2 | Negative |
Following a skin biopsy on the patient's right forearm, acid-fast bacilli were identified in the deep dermis and subcutis, suggestive of mycobacterial infection (Fig. 4). Absence of granulomas, leukemic infiltrate, or graft-versus-host disease was noted. Subsequent molecular testing utilizing 16S rRNA and hsp65 sequencing definitively identified the presence of Mycobacterium haemophilum. Concurrently, Mycobacterium haemophilum was isolated from the patient's sputum and stool samples, corroborating the systemic dissemination of the infection.
A positron emission tomography-computed tomography (PET-CT) scan revealed new hypermetabolic lesions in various locations, including the left inferior turbinate, lymph nodes (left cervical level IIA, left level IB, right level VA, left supraclavicular fossa), and subcutaneous areas (left leg, right thigh, left arm, dorsum of right hand, right ear). Additionally, generalized increased uptake in the spleen was observed. Based on these findings, the patient was diagnosed with disseminated Mycobacterium haemophilium infection.
The patient received comprehensive care from a multidisciplinary team comprising infectious disease physicians, dermatologists, and haematologists in our hospital. The infectious disease physician prescribed Rifabutin 300mg PO daily, Levofloxacin 500 mg PO daily, and Clarithromycin 500mg PO BD as treatment. The haematologist promptly reduced the Prednisolone dosage and tapered off the Mycophenolate mofetil and sirolimus medications the patient had been taking.
Following two weeks of treatment, the patient experienced recurring fever, particularly at night, along with the emergence of new erythematous nodules on his face and upper back (Fig. 5). To further investigate, a repeated skin biopsy was conducted on his upper back, revealing granulomatous inflammation (Fig. 6). However, multiple Ziehl-Neelsen stain assessments did not indicate the presence of acid-fast bacilli (Fig. 7). Additionally, a thorough septic workup, inclusive of blood, sputum, urine, and stool cultures, yielded negative results.
The decline in AFB load in sputum and reappearance of granulomatous inflammation indicated a recovery of immune function, suggesting a diagnosis of Immune Reconstitution Inflammatory Syndrome (IRIS) instead of a drug-resistant mycobacterial infection. The patient's treatment regimen was changed to include Prednisolone 35mg daily in addition to continued levofloxacin, rifabutin, and clarithromycin. After one week, the patient's fever subsided and the erythematous rash on their trunk, face, and scalp significantly improved. Inflammatory markers showed a downward trend. The Prednisolone dosage was gradually reduced to 5mg daily.